Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic islet encapsulation into synthetic, passive material matrixes can provide protection for transplanted islets from destruction via cell-contacted mediated interactions with autoreactive immune cells for treatment of Type I diabetes mellitus. However, one of the fundamental deficiencies with current encapsulation technology is that passive material barriers cannot protect islets from exposure to cytokines and other small, diffusible cytotoxic molecules produced by activated immune cells, subsequently leading to beta-cell destruction. Preparation of material matrixes that can actively provide localized immunosuppression of autoreactive immune cells may prolong the viability, and hence function, of encapsulated islet grafts. We have demonstrated the ability to conjugate apoptosis-inducing anti-Fas monoclonal antibodies (MAbs) to the surfaces of poly(ethylene glycol)-modified hydrogels, providing a surface that actively attempts to locally down-regulate the autoimmune response by destroying autoreactive T cells against pancreatic islet cells. We have conjugated anti-Fas MAbs to a high degree to the surface of these hydrogels, with retention of anti-Fas recognition of the Fas antigen as shown by ELISA testing. Apoptosis induction of Fas-sensitive Jurkat T cells was enhanced in the presence of anti-Fas conjugated hydrogels. In addition, this apoptosis induction was specific to anti-Fas MAbs, with no apoptosis induction with control antibodies or with Fas-insensitive T cells. These experiments promote the concept that surface-conjugated hydrogel constructs can provide localized immunosuppression for encapsulated grafted tissue.
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PMID:Synthesis of immunoisolation barriers that provide localized immunosuppression for encapsulated pancreatic islets. 1684 13

Pig islets are considered to be most suitable source of islets for xenotransplantation into patients with type 1 diabetes mellitus. However, cellular rejection, especially CD8+ CTL-mediated cytotoxicity, remains a formidable barrier preventing long-term xenograft survival. Our previous study demonstrated that human CD8+ CTLs were highly detrimental to xenograft cells and that this strong cytotoxicity of human CTLs was mediated mainly by the Fas/FasL apoptotic pathway. Furthermore, we exploited novel methods for inhibiting human CD8+ CTL-mediated xenocytotoxicity with overexpression of membrane-bound human FasL and human decoy Fas antigen in xenografted cells. In the present study, we assessed the cytoprotective effects of these novel inhibitory molecules overexpressed by an adenoviral-mediated system in pig islets. Isolated pig islets were transfected with adenovirus vector encoding either human decoy Fas or membrane-bound human FasL genes. Thirty percent to 60% of transfected pig islets expressed these molecules producing 60% to 88% suppression of CTL killing compared with parental pig islets. These data indicated that pig islet grafts isolated from transgenic pigs with either membrane-bound human FasL or human decoy Fas antigen genes may control the innate cellular response to xenografts, and creating a window of opportunity to facilitate xenograft survival.
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PMID:Adenoviral-mediated overexpression of membrane-bound human FasL and human decoy Fas protect pig islets against human CD8+ CTL-mediated cytotoxicity. 1717 51

Pancreatic tissues were analyzed immunohistologically in patients with autoimmune and fulminant type 1 diabetes (T1D) and control subjects. Both beta and alpha cells were decreased in fulminant T1D, but only beta cells were significantly decreased in autoimmune T1D. Insulitis was seen in both subtypes of T1D, but it remained longer in autoimmune than in fulminant T1D. Lymphocytic infiltration to the exocrine pancreatic tissue was observed only in fulminant T1D, whereas immunologically abnormal findings, such as increased expression of MHC class I molecule and Fas antigen in islet cells and Fas-ligand expression in infiltrating lymphocytes, were detected only in autoimmune T1D. From these findings, together with clinical features, it could be concluded that in autoimmune T1D, beta cells are assumed to be destroyed through a long-standing autoimmune process, whereas in fulminant T1D, beta cells seem to be destroyed very rapidly, probably by a destructive process triggered by viral infection.
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PMID:Insulitis in human type 1 diabetes. 1912 Mar 16

The critical problem with clinical islet transplantation for patients with type 1 diabetes is the severe shortage of human donors. Pig islet xenotransplantation has the potential to provide a virtually unlimited source of donor pancreata. However, our previous studies demonstrated that cell-mediated rejection, especially human CD8(+) cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, remains a major obstacle for long-term islet xenograft survival. Moreover, we have demonstrated that the overexpression of either membrane-bound human FasL (mFasL) or human decoy Fas antigen (decoy Fas) in pig islets not only prevented CTL xenocytotoxicity in vitro, but also prolonged histological survival of pig islet xenografts in vivo. Therefore, the aim of the present study was to determine whether adenoviral transfer of these genes into pig islets ex vivo prior to transplantation had a beneficial effect on posttransplantation glycemic control of diabetic recipients. Isolated pig islets were transfected with adenovirus vector carrying complementary DNA (cDNA) of either mFasL or decoy Fas. The transfected islets were transplanted under the kidney capsule of diabetic recipient rats. Rats transplanted with either mFasL- or decoy Fas-transfected pig islet grafts showed significantly suppressed blood glucose levels from 12 hours to 18 hours posttransplantation compared with control groups transplanted with empty vector-transfected pig islets. Unfortunately, blood glucose levels of these groups were increased, with no significant difference observed at 24 hours posttransplantation. However, transgenic expression of these molecules with clinically tolerable amount of immunosuppressants may be more effective to achieve islet xenograft survival in the future.
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PMID:In vivo controlling of cellular response to pig islet xenografts by adenovirus-mediated expression of either membrane-bound human FasL or human decoy Fas. 1924 49